Method of administering therapeutic agents



United States Patent 3,474,777 METHOD OF ADMINISTERING THERAPEUTIC AGENTS Frank H. J. Figge, Towson, Md., and Guiles Flower, In,

Carlisle, Pa., assignors to AMP Incorporated, Harrisburg, Pa., a corporation of New Jersey N0 Drawing. Filed Feb. 10, 1966, Ser. No. 526,361 Int. Cl. A6111 5/00; A6111 5/10 U.S. Cl. 128-22 13 Claims ABSTRACT OF THE DISCLOSURE Method of localizing a therapeutic agent at a preferred treatment site within an organism by injecting said agent into the organism in association with a magnetically responsive substance and concentrating the agent and substance at the preferred treatment site by the application of magnetic fields to the organism. Microcapsules and/or particles adaptable to injection and having a maximum size of five microns, said microcapsules and/ or particles comprising a therapeutic agent in association with a magnetically responsive substance.

This invention relates to methods of localizing a therapeutic agent at a preferred treatment site within an organism and to therapeutic agents for use in practising such methods.

Numerous therapeutic substances, while exerting beneficial eifects on certain portions of a diseased organism, may detrimentally aflfect other, healthy, portions of the organism. If therapeutic agents of this type are localized within the organism at those sites specifically desired to be treated with the therapeutic agent, without being dispersed generally throughout the organism, the beneficial effect of the therapeutic agent is maximized while possibly harmful elfects are minimized or eliminated.

The present invention relates to a method of localizing a threapeutic agent at a preferred treatment site within an organism by introducing said therapeutic agent into the organism in association with a magnetically responsive substance. The magnetically responsive substance and the therapeutic agent are then directed, localized, or concentrated within the organism under the influence of magnetic fields applied to the organism or to those portions of the organism to be treated. When the therapeutic agent is thus localized within the organism in association with a magnetically responsive substance, the position or location of which substance in turn is controlled by the applied magnetic field, the therapeutic agent acts locally without being generally dispersed throughout the organism. Subsequently, the therapeutic agent and associated magnetic substance can be recovered from the organism, if their continued presence is unnecessary ordetrimental, by methods discussed hereinafter. In other embodiments, the therapeutic agent and magnetic substance are dissociated within the organism, and only the magnetic substance is recovered.

By therapeutic agent herein is meant, broadly, a substance or substances having an ultimate beneficial effeet on an organism. Thus, the term as used in the present specification and claims may include materials, such. as radioactive substances, which are harmful to or destructive of living tissue. The use of such radioactive materials to destroy abnormal tissue, however, would constitute an ultimate beneficial effect to the organism and such substances are considered herein as therapeutic agents.

By a magnetically responsive substance as used in the specification and claims of this application is meant a material which responds to and/or can be directed spatially by a magnetic field or fields. The responsive substances need not be paramagnetic, although such substances are most commonly thought of as being magnetic in the conventional sense, but may also be diamagnetic. The materials may be elements or compounds, or components of compounds, and need have no particular physical form providing only that they can be influenced in their direction of movement by a magnetic field.

The association between the therapeutic agent and the magnetically responsive substance may be of diverse types. Most commonly, the agent and magnetic substance are associated together in the form of discrete particles, which particles may have the form of microcapsules. Thus, a magnetically responsive substance as understood herein may be coated with or dispersed within a therapeutic agent or, conversely, a magnetically responsive substance may be used to coat or partially coat a therapeutic agent, or as a matrix for the agent. When the particles are employed in the form of microcapsules, the magnetically responsive substance may be within the capsule shell, or the magnetic substance may form part of a shell encapsulating a therapeutic agent. In still a further embodiment, the association between the therapeutic agent and the magnetically responsive substance may be on an atomic scale, for instance where the therapeutic agent comprises a radioactive isotope prepared by irradiation or bombardment of particles of a magnetically responsive substance. In such a case, the radioactive therapeutic agent, comprising a transmuted form of the magnetically responsive substance, is dispersed atomically throughout the magnetically responsive substance. Finally, the therapeutic agent and magnetically responsive substance may be one and the same, as in the case of magnetic radioactive isotopes.

U.S. Patent 2,971,916, for example, discloses the manufacture of microscopic capsules comprising a magnetizable material. U.S. Patent 3,042,416 discloses the coating of magnetic particles of very small diameter. U.S. Patent 3,190,837 discloses methods of encapsulating various materials, specifically including solid magnetic materials.

For localization within the capillary bed of animal tissue, particles comprising a therapeutic agent and an associated magnetically responsive substance should be sufficiently small to pass freely through the capillaries. In the mouse and many other vertebrates, for example, average capillary diameter is about 78 microns, a size accommodating the red blood cells, which are about seven microns in size. Hence, for use in mice, for example, therapeutiomagnetic particles of the type contemplated by the invention would suitably have an average size of up to about 5 microns. Since about twothirds of the capillary vessels within a capillary bed are not normally engorged with blood except when circulation is stimulated by exercise, there is little chance of complete blockage of all the blood vessels of a capillary bed on introduction thereinto of particles of the type described. Also, during treatment, the particles can be moved within the capillaries by movement or rotation of the magnetic field to alter the position of the magnetically responsive particles during treatment. As will be evident to those skilled in the art, the magnetically responsive substances, and/or other inert substances having no therapeutic effect but used as coatings, to form capsule shell walls, etc. should be materials compatible with the organism, e.g. substances compatible with animal body fluids, or not forming clots when present in the blood stream of animals.

In the present invention, such microscopic particles are introduced into the organism by injection. The introduction of a therapeutic agent into the capillary bed of animal tissue is of particular importance, and may be effected either by intravenous injection or injection into an artery.

One injected into the organism, the therapeutic agent may be localized by control of the magnetically responsive substance in association therewith under the influence of applied magnetic fields. As will be evident to those skilled in the art, the magnetic fields may be established by permanent magnets, or by electromagnets, and may be altered in size, shape, and strength to adapt them to particular situations. The detection of localization of the magnetically responsive substance and associated therapeutic agent may be done by chemical analysis. Fluoroscopic or roentgenographic examination of the organism also offers a ready means of detection, since the magnetically responsive substances are commonly relatively opaque to X-rays.

Dissociation or release of a therapeutic agent from a magnetic substance is preferably initiated or promoted, if appropriate, after the therapeutic agent has been localized in an organism by magnetic direction of the magnetically responsive substance associated therewith. This dissociation may merely involve the lapse of time, as, for example, in the loss of the therapeutic properties of a radioactive isotope by partial or complete radioactive decay. Dissociation may also be effected by external agencies, such as the use of high frequency sound waves to rupture the coatings of microcapsules containing a therapuetic agent within the capsules. Most commonly, release of the therapeutic agent is effected by some agency internal to the organism. For example, a therapeutic coating on a magnetically responsive substance may simply be released with time by solution of the therapeutic agent in natural fluids of the organisms. Further, the release of a therapeutic agent from association with a magnetic substance may be initiated or speeded in response to still another substance injected or ingested into the organism after localization of the therapeutic agent in situ has been effected.

After therapeutic treatment has been completed, or the therapeutic agent and magnetically responsive substance have been dissociated, the magnetically responsive substance may be recovered from the organism if its continued presence is undesirable. For example, in an animal, magnetic fields localizing magnetic particles in particular tissues may be removed, permitting the particles to circulate in the blood stream. By passing the blood through a magnetic trap external to the organism, the particles can be localized to simplify their removal. Permitting the blood to pass through a simple T-tube connection in which one arm of the T is maintained in a magnetic field will cause magnetically responsive substances in the blood to be attracted by the magnetic field and to be retained in the arm of the tube. The substances are thus isolated from the blood of the animal.

The methods of the present invention can be utilized for the administration of local anesthesia, for example, both within tissues generally or in the spinal fluid of a vertebrate. Endocrine glands can be stimulated or inhibited by the administration of drugs or other endocrine substances whose effects are localized in the glands. Cortisone or cortisone-like substances, for example, can be administered directly to rheumatic joints while minimizing side effects such as ulcers, edema, and endocrine upset associated with general dispersal of cortisone through an animal organism. Abnormal or cancerous tissue can also be treated.

Such abnormal tissue can presently be destroyed, or the cells thereof rendered incapable of further reproduction, by a variety of compounds known to the art, including materials such as 6-mercaptopurine, buslfan, chlorambucil, methotrexate, nitrogen mustards, azetepa, fluorouracil, or 5-fluoro-deoxyuridine. Compounds of this type,

although highly effective in destroying unwanted tissue, also attack tissue in other portions 'of the organism since they must, in the present state of the art, be introduced into the blood stream and dispersed generally throughout the organism. -In many cases, the maximum dose of such a therapuetic agent which can be administered is determined solely by the maximum detrimental effect which can be tolerated by portions of the organism other than that being treated. Using the methods of the present invention, the severe side effects of these drugs on healthy tissue can be minimized without loss of effect on abnormal tissue being treated.

What is claimed is:

1. The method of localizing a therapeutic agent at a preferred treatment site within an organism which comprises injecting said agent into said organism in association with a magnetically responsive substance and concentrating said agent and substance at said preferred treatment site by the application of magnetic fields to said organism.

2. The method as in claim 1 wherein said therapeutic agent and associated magnetically responsive substance are associated in a plurality of microscopic particles.

3. The method as in claim 2 wherein said microscopic particles comprise microcapsules.

4. The method as in claim 1 wherein said magnetically responsive substance is said therapeutic agent.

5. The method as in claim 1 wherein said therapeutic agent and associated magnetically responsive substance dissociate with time.

6. The method as in claim 1 wherein said therapeutic agent and associated magnetically responsive substance dissociate in response to an agency external to said organism.

7. The method as in claim 1 wheren said therapeutic agent and associated magnetically responsive substance dissociate in response to an agency within said organism.

8. The method as in claim 1 wherein said therapeutic agent comprises a radioactive isotope.

9. The method as in claim 1 wherein said therapeutic agent comprises a substance antagonistic to abnormal cell growth.

10. Microcapsules adaptable to injection and having a maximum particle size of about five microns, said microcapsules comprising a therapeutic agent in association with a magneticaly responsive substance.

11. Finely-divided particles of a magnetically responsive substance having a coating of a therapeutic agent thereon, said particles being adaptable to injection and having a maximum particle size of about five microns.

12. Microcapsules as in claim 10 wherein said therapeutic agent comprises a substance antagonistic to abnormal cell growth.

13. Particles as in claim 11 wherein said therapeutic agent is a substance antagonistic to abnormal cell growth.

References Cited UNITED STATES PATENTS 2,671,451 3/1954 Bolger 12826O 3,057,344 10/1962 Abella et a1. 128-2 3,159,545 12/1964 Kidwell et al. 16751 X OTHER REFERENCES Injection Gun: Cancer treatment tester, Washington Post, Feb. 1, 1968.

ADELE M. EAGER, Primary Examiner US. Cl. X.R. 

